Department of Vascular Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China.
Vascular Center of Shanghai Jiao Tong University, Shanghai 200011, China.
Oxid Med Cell Longev. 2023 Jan 27;2023:8134027. doi: 10.1155/2023/8134027. eCollection 2023.
N6-methyladenosine (m6A) is one of the most prevalent, abundant, and internal transcriptional modification and plays essential roles in diverse cellular and physiological processes. Low fluid shear stress (FSS) is a key pathological factor for many cardiovascular diseases, which directly forces on the endothelial cells of vessel walls. So far, the alterations and functions of m6A modifications in vascular endothelial cells at the low FSS are still unknown. Herein, we performed the transcriptome-wide m6A modification profiling of HUVECs at different FSS. We found that the m6A modifications were altered earlier and more sensitive than mRNA expressions in response to FSS. The low FSS increased the m6A modifications at CDS region but decreased the m6A modifications at 3' UTR region and regulated both the mRNA expressions and m6A modifications of the m6A regulators, such as the RBM15 and EIF3A. Functional annotations enriched by the hypermethylated and hypomethylated genes at low FSS revealed that the m6A modifications were clustered in the aging-related signaling pathways of mTOR, PI3K-AKT, insulin, and ERRB and in the oxidative stress-related transcriptional factors, such as HIF1A, NFAT5, and NFE2L2. Our study provided a pilot view of m6A modifications in vascular endothelial cells at low FSS and revealed that the m6A modifications driven by low FSS mediated the cellular responses to oxidative stress and cell aging, which suggested that the m6A modifications could be the potential targets for inhibiting vascular aging at pathological low FSS.
N6-甲基腺苷（m6A）是最普遍、最丰富和最内部的转录修饰之一，在多种细胞和生理过程中发挥着重要作用。低流体切应力（FSS）是许多心血管疾病的关键病理因素，它直接作用于血管壁的内皮细胞。迄今为止，低 FSS 下血管内皮细胞中 m6A 修饰的改变和功能仍不清楚。在此，我们对不同 FSS 下的 HUVECs 进行了全转录组 m6A 修饰谱分析。我们发现，m6A 修饰比 mRNA 表达对 FSS 的响应更早且更敏感。低 FSS 增加了 CDS 区域的 m6A 修饰，但减少了 3'UTR 区域的 m6A 修饰，并调节了 m6A 调节因子的 mRNA 表达和 m6A 修饰，如 RBM15 和 EIF3A。由低 FSS 下高甲基化和低甲基化基因富集的功能注释表明，m6A 修饰聚类在 mTOR、PI3K-AKT、胰岛素和 ERRB 的衰老相关信号通路以及 HIF1A、NFAT5 和 NFE2L2 等与氧化应激相关的转录因子中。我们的研究提供了低 FSS 下血管内皮细胞中 m6A 修饰的初步视图，并揭示了低 FSS 驱动的 m6A 修饰介导了细胞对氧化应激和细胞衰老的反应，这表明 m6A 修饰可能是抑制病理低 FSS 下血管衰老的潜在靶点。
